Research Spotlight

Posted May 21st 2021

High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring.

Teodoro Bottiglieri, Ph.D.

Teodoro Bottiglieri, Ph.D.

Pannia, E., Hammoud, R., Kubant, R., Sa, J.Y., Simonian, R., Wasek, B., Ashcraft, P., Bottiglieri, T., Pausova, Z. and Anderson, G.H. (2021). “High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring.” Nutrients 13(5).

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Supplementation with [6S]-5-methyltetrahydrofolic acid (MTHF) is recommended as an alternative to folic acid (FA) in prenatal supplements. This study compared equimolar gestational FA and MTHF diets on energy regulation of female offspring. Wistar rats were fed an AIN-93G diet with recommended (2 mg/kg diet) or 5-fold (5X) intakes of MTHF or FA. At weaning, female offspring were fed a 45% fat diet until 19 weeks. The 5X-MTHF offspring had higher body weight (>15%), food intake (8%), light-cycle energy expenditure, and lower activity compared to 5X-FA offspring (p < 0.05). Both the 5X offspring had higher plasma levels of the anorectic hormone leptin at birth (60%) and at 19 weeks (40%), and lower liver weight and total liver lipids compared to the 1X offspring (p < 0.05). Hypothalamic mRNA expression of leptin receptor (ObRb) was lower, and of suppressor of cytokine signaling-3 (Socs3) was higher in the 5X-MTHF offspring (p < 0.05), suggesting central leptin dysregulation. In contrast, the 5X-FA offspring had higher expression of genes encoding for dopamine and GABA- neurotransmitter receptors (p < 0.01), consistent with their phenotype and reduced food intake. When fed folate diets at the requirement level, no differences were found due to form in the offspring. We conclude that MTHF compared to FA consumed at high levels in the gestational diets program central and peripheral mechanisms to favour increased weight gain in the offspring. These pre-clinical findings caution against high gestational intakes of folates of either form and encourage clinical trials examining their long-term health effects when consumed during pregnancy.


Posted May 21st 2021

Choline and Folic Acid in Diets Consumed during Pregnancy Interact to Program Food Intake and Metabolic Regulation of Male Wistar Rat Offspring.

Teodoro Bottiglieri, Ph.D.

Teodoro Bottiglieri, Ph.D.

Hammoud, R., Pannia, E., Kubant, R., Wasek, B., Bottiglieri, T., Malysheva, O.V., Caudill, M.A. and Anderson, G.H. (2021). “Choline and Folic Acid in Diets Consumed during Pregnancy Interact to Program Food Intake and Metabolic Regulation of Male Wistar Rat Offspring.” J Nutr 151(4): 857-865.

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BACKGROUND: North American women consume high folic acid (FA), but most are not meeting the adequate intakes for choline. High-FA gestational diets induce an obesogenic phenotype in rat offspring. It is unclear if imbalances between FA and other methyl-nutrients (i.e., choline) account for these effects. OBJECTIVE: This study investigated the interaction of choline and FA in gestational diets on food intake, body weight, one-carbon metabolism, and hypothalamic gene expression in male Wistar rat offspring. METHODS: Pregnant Wistar rats were fed an AIN-93G diet with recommended choline and FA [RCRF; 1-fold, control] or high (5-fold) FA with choline at 0.5-fold [low choline and high folic acid (LCHF)], 1-fold [recommended choline and high folic acid (RCHF)], or 2.5-fold [high choline and high folic acid (HCHF)]. Male offspring were weaned to an RCRF diet for 20 wk. Food intake, weight gain, plasma energy-regulatory hormones, brain and plasma one-carbon metabolites, and RNA sequencing (RNA-seq) in pup hypothalamuses were assessed. RESULTS: Adult offspring from LCHF and RCHF, but not HCHF, gestational diets had 10% higher food intake and weight gain than controls (P < 0.01). HCHF newborn pups had lower plasma insulin and leptin compared with LCHF and RCHF pups (P < 0.05), respectively. Pup brain choline (P < 0.05) and betaine (P < 0.01) were 22-33% higher in HCHF pups compared with LCHF pups; methionine was ∼23% lower after all high FA diets compared with RCRF (P < 0.01). LCHF adult offspring had lower brain choline (P < 0.05) than all groups and lower plasma 5-methyltetrahydrofolate (P < 0.05) than RCRF and RCHF groups. HCHF adult offspring had lower plasma cystathionine (P < 0.05) than LCHF adult offspring and lower homocysteine (P < 0.01) than RCHF and RCRF adult offspring. RNA-seq identified 144 differentially expressed genes in the hypothalamus of HCHF newborns compared with controls. CONCLUSIONS: Increased choline in gestational diets modified the programming effects of high FA on long-term food intake regulation, plasma energy-regulatory hormones, one-carbon metabolism, and hypothalamic gene expression in male Wistar rat offspring, emphasizing a need for more attention to the choline and FA balance in maternal diets.


Posted May 21st 2021

Associations of childhood trauma and executive functioning in everyday life of those with subjective cognitive complaints.

Jared F. Benge, Ph.D.

Jared F. Benge, Ph.D.

Lantrip, C., Szabo, Y.Z., Pazienza, S. and Benge, J. (2021). “Associations of childhood trauma and executive functioning in everyday life of those with subjective cognitive complaints.” Appl Neuropsychol Adult: 1-9.

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Subjective cognitive complaints are a frequent patient-reported problem. Some adults with cognitive complaints present to the neuropsychology clinic without a diagnosable cognitive disorder but experience subjective daily executive dysfunction. It is well-established that trauma may impact executive function; however, the nuances of this relationship remain of interest. The present study descriptively reports associations between executive function and childhood trauma as well as lifetime trauma and current posttraumatic stress disorder (PTSD) symptoms. Participants were 48 adults referred to a neuropsychology clinic for evaluation without an identified neurocognitive disorder. Correlations between self-reported executive dysfunction, as assessed by the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), childhood trauma as measured by the Childhood Trauma Questionnaire and lifetime and current symptoms using the PTSD Diagnostic Scale for Diagnostic and Statistical Manual of Mental Disorders-5 were conducted. Correlations indicated that emotional neglect was associated with BRIEF-A indices and specific subscales including self-monitoring, shifting attention, task initiation, and planning/organization. Childhood emotional and sexual abuse and physical neglect and abuse, lifetime trauma and current PTSD symptoms were not associated with BRIEF-A indices. Though preliminary, these results highlight that in this population, history of childhood emotional neglect is particularly important when considering etiology of daily executive function complaints. Clinical implications and limitations are discussed.


Posted May 21st 2021

Neuropsychological impact of white matter hyperintensities in older adults without dementia.

Jared F. Benge, Ph.D.

Jared F. Benge, Ph.D.

Chavda, R., Cao, J.S. and Benge, J.F. (2021). “Neuropsychological impact of white matter hyperintensities in older adults without dementia.” Appl Neuropsychol Adult 28(3): 354-362

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The purpose of this study was to determine (a) if simple clinical judgements of white matter hyperintensities (WMH) on imaging are associated with measurable cognitive impacts in otherwise cognitively normal older adults, (b) if neuropsychological measures can predict those with WMH, and (c) the frequency of low cognitive scores in those with WMH on a battery of measures. Forty-four individuals judged free of other cognitive disorders despite moderate to extensive WMH were compared with 50 individuals matched on age (mean of 83), education (college educated), and gender (predominantly female). Data was obtained from the National Alzheimer’s Coordinating Center database. The group with at least moderate WMH had lower scores on the Trail Making Test A, verbal fluency, and digit span. A component score derived from these measures was a significant predictor of the presence of WMH, though only correctly classified 68% of participants. Even in individuals free from other suspected conditions, clinically judged moderate to extensive WMH was associated with cognitive weaknesses for processing speed, working memory, and executive functioning. This shows that a relatively simple judgment of WMH burden is meaningfully associated with worse cognition. Implications and future directions for are discussed.


Posted May 21st 2021

ACR Appropriateness Criteria® Radiologic Management of Portal Hypertension.

Sumeet K. Asrani M.D.

Sumeet K. Asrani M.D.

Pinchot, J.W., Kalva, S.P., Majdalany, B.S., Kim, C.Y., Ahmed, O., Asrani, S.K., Cash, B.D., Eldrup-Jorgensen, J., Kendi, A.T., Scheidt, M.J., Sella, D.M., Dill, K.E. and Hohenwalter, E.J. (2021). “ACR Appropriateness Criteria® Radiologic Management of Portal Hypertension.” J Am Coll Radiol 18(5s): S153-s173.

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Cirrhosis is a heterogeneous disease that cannot be studied as a single entity and is classified in two main prognostic stages: compensated and decompensated cirrhosis. Portal hypertension, characterized by a pathological increase of the portal pressure and by the formation of portal-systemic collaterals that bypass the liver, is the initial and main consequence of cirrhosis and is responsible for the majority of its complications. A myriad of treatment options exists for appropriately managing the most common complications of portal hypertension, including acute variceal bleeding and refractory ascites. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.